Sepsis Alert Systems, Mortality, and Adherence in Emergency Departments

Key Points Question Are sepsis alert systems, including electronic clinical decision supports and manual notifications, associated with mortality and adherence to the Surviving Sepsis Campaign sepsis bundle for initial treatment of patients in the emergency department? Findings In this systematic review and meta-analysis including 22 studies of 19 580 patients, sepsis alert systems were associated with lower mortality, a shorter hospital stay, and improved sepsis-bundle adherence, notably in terms of shorter time to fluid administration, blood culture, antibiotic administration, and lactate measurement. Electronic alerts were particularly associated with reducing mortality and time to blood culture. Meaning This systematic review and meta-analysis found that sepsis alert systems were associated with better outcomes and adherence with sepsis management in emergency departments.


Introduction
Sepsis is a major global health problem associated with high mortality and morbidity rates among hospitalized patients. 1,2A recent global analysis estimated that sepsis accounted for 11 million deaths in 2017, accounting for 19.7% of all deaths worldwide. 3To improve the quality of sepsis management, the Surviving Sepsis Campaign (SSC) developed an evidence-based bundle comprising 5 elements to be implemented within the first hours of sepsis recognition. 4These elements include fluid resuscitation with 30 mL/kg of crystalloid, blood culture before antibiotic administration, broadspectrum antibiotic therapy, lactate measurement, and vasopressor support for refractory hypotension.Adherence to the sepsis bundle has demonstrated improved clinical outcomes in patients, [5][6][7] despite the varying quality of evidence supporting some of the elements.
Patients with sepsis who visit the emergency department (ED) exhibit high rates of hospitalization (70%) and mortality (10%).The ED is the main point of entry for hospital admission in this population. 8,9Timely diagnosis and treatment of sepsis are critical, as delays can significantly increase the risk of mortality and morbidity. 5,10However, ED staff face challenges in promptly identifying and effectively managing sepsis due to the frequent overcrowding of patients in need of urgent care. 11To address these challenges, sepsis alert systems have emerged as potential solutions to facilitate the early recognition of sepsis in the ED.Several studies have investigated the role of sepsis alert systems in improving the early identification of sepsis in patients in the ED.A 2020 systematic review examined the diagnostic accuracy of sepsis alert systems and found that they had acceptable sensitivity for identifying patients with sepsis. 12However, the clinical impact of sepsis alert systems on patient outcomes, including mortality rates and timelines of sepsis management in the ED, remains unclear.
Therefore, we conducted a systematic review and meta-analysis to assess the association of sepsis alert systems with mortality and adherence to the SSC sepsis bundle for the initial management of patients with sepsis in the ED.By synthesizing the available evidence, we aimed to provide insights into the potential benefits of sepsis alert systems in improving clinical outcomes and optimizing sepsis management in the challenging ED environment.

Search Strategy
For this systematic review and meta-analysis, the study protocol was registered in PROSPERO (record identifier: 341106).We searched PubMed, EMBASE, Web of Science, and the Cochrane Library with keywords, such as emergency department, and sepsis alert system.Because the SSC was launched in 2004, we only considered studies published after that date. 13The search was conducted on November 19, 2023, using a structural search plan (eAppendix in Supplement 1).][16]

Study Selection and Definition of Outcomes
All study designs were included.Sepsis alert systems were defined as interventions using mechanisms to facilitate early sepsis identification and treatment.Titles and abstracts were reviewed to identify studies that qualified for full-text evaluation.We selected only peer-reviewed English full-text articles with eligible target patients (adult patients with sepsis in the ED), the appropriate intervention (alert systems for sepsis), comparators (absent alert system), and outcomes that were presented in numbers.We evaluated the outcomes that may be associated with sepsis alert systems, such as death, intensive care unit (ICU) admission, hospital length of stay (LOS), and adherence to the SSC sepsis bundle (intravenous [IV] fluid administration, acquisition of blood culture, antibiotic administration, and lactate measurement).

Data Extraction
We collected data from each study, including author names, study duration, country, study design, number of patients, and target patients.Each study's detailed description included the criteria of the alert system, the method of alert delivery, and subsequent interventions.As the definitions of each outcome (death, ICU admission, hospital LOS, and adherence to each sepsis bundle) varied among the studies, the definitions in each study were also described.
Information was categorized based on type.The input variables for the categorical variables were organized in a 2-by-2 table.For continuous variables, means and SDs were calculated, as suggested by the Cochrane Handbook. 17

Statistical Analysis
Using forest plots and a random-effects model, we investigated the baseline characteristics and the association of each variable with outcomes.I 2 statistics were used to determine the heterogeneity levels.Pooled risk ratios (RRs) were calculated for categorical variables.Owing to differences in scales, standardized mean differences (SMDs) were calculated for continuous variables.SMDs describe the effect size relative to the variability observed in each study, facilitating comparisons across studies with different scales or units.For example, if the SD is 1 hour, an SMD of −0.5 implies treatment occurs approximately 30 minutes sooner.The 95% CIs for each pooled value were calculated.The statistical analyses in this meta-analysis were guided by a predefined significance level of P < .05,using 2-sided tests.According to the recommended risk of bias in nonrandomized studies of interventions (ROBINSON-I) protocol, 18 the risk of bias in each study was assessed for the following 7 domains: bias due to confounding factors, selection of participants, classification of interventions, deviations from intended interventions, missing data, measurement of outcomes, and selection of reported results.Egger regression test was used to assess publication bias. 19 planned a subgroup analysis based on the type of alert system (electronic alert vs nonelectronic alert) to assess the differential associations of sepsis alert systems.Electronic alerts referred to automated alerts, such as pop-up windows in electronic health records (EHRs), while nonelectronic alerts referred to manual interventions, like broadcasting notifications within the ED.
Due to significant heterogeneity in the time to implement each bundle approach, we performed additional subgroup analyses including only studies with a low risk of bias.
Two independent reviewers (H.-J.K. and R.-E.K.) performed study screening, data extraction, and assessment of quality and risk of bias, and a consensus was reached through group discussion.

Association of Sepsis Alerts With Sepsis Bundle Adherence
Studies that explicitly specified time limits were included in the analysis of the association of sepsis alerts with sepsis bundle adherence.Time zero had different definitions in each study; it was defined as the point of ED admission (9 studies 22,[25][26][27]32,36,38,39,41 ), the point of triage (6 studies 20,21,23,28,35,37 ), the point at which the first set of vital signs was obtained (2 studies 29,30 ), the time of the alert alarm (1 study 34 ), the point of recognition of sepsis (1 study 33 ), the point of the earliest EHR annotation consistent with all elements of severe sepsis or septic shock (1 study 31 ), or when the patient met specific criteria (2 systemic inflammatory response syndrome criteria: evidence of end-organ dysfunction and a suspected infection [1 study 24 ]). The remaining tudy 40 did not specify the definition of time zero (Supplement 2).
As a whole, application of the sepsis alert system was associated with a higher rate of adherence to each element of the sepsis bundle (Table 2).The subgroup analyses (electronic vs nonelectronic alert) yielded results similar to those of the main analysis methods for most outcomes, except for mortality and blood culture (Table 2).The electronic alert system was associated with reduced mortality (RR, 0.78; 95% CI, 0.67 to 0.92) and adherence to blood culture guidelines (RR, 1.14; 95% CI, 1.03 to 1.27), whereas the nonelectronic alert systems showed no notable difference.

Discussion
This systematic review and meta-analysis aimed to assess the association of sepsis alert systems with mortality risk and adherence to the sepsis bundle for the initial management of patients with sepsis in the ED.The main findings of this study can be summarized as follows: (1) patient mortality risk was significantly associated with the presence of sepsis alert systems, (2) sepsis alert systems were associated with enhanced adherence to the sepsis bundle and a shorter time to delivery of each bundle element, and (3) the sepsis alert systems had more associations for the electronic alert group than for the nonelectronic alert group.

JAMA Network Open | Critical Care Medicine
Sepsis Alert Systems, Mortality, and Adherence in Emergency Departments usual care.However, another meta-analysis of 16 studies by Joshi et al 43 that evaluated the associations of sepsis alert systems in the ED and general wards found no significant association with mortality reduction.The conflicting results may be due to the heterogeneity of patients with sepsis targeted by these meta-analyses.In contrast, we included only ED settings to ensure a similar context for the recognition and management of sepsis.We found that the sepsis alert system was significantly associated with lower mortality and a shorter hospital LOS, which is consistent with the findings from Joshi et al. 43 The implementation of the sepsis alert system was associated with a shorter time to intervention for all 4 elements of the sepsis bundle.Previous meta-analyses on this topic also attempted to evaluate adherence to elements of the sepsis bundle but were limited to the time to antibiotic administration.Joshi et al 43 found no significant difference in antibiotic timing between groups with and without a sepsis alert system based on 5 studies.However, in another systematic review, Hwang et al 12 reported that sepsis alert systems might reduce the time to antibiotics.
Reducing the time interval from the recognition of sepsis to the implementation of the sepsis bundle is a crucial indicator of the quality of care in initial sepsis management. 7,44However, this measure is challenging due to the inconsistency in determining time zero. 12,42,43,45Hence, our study aimed to evaluate the association of sepsis alert systems with the time interval from the recognition of sepsis to the implementation of the sepsis bundle by focusing only on patients in the ED, which enabled a more precise definition of time zero.However, we acknowledge that the definition of time zero in the included studies was not uniform.A key objective for future research is to standardize the definition of time zero in patients with sepsis, especially in the general ward and ICU, as this would enable a more accurate analysis of sepsis outcomes across different settings.Despite substantial publication bias regarding the time to blood culture and time to lactate measurement, to our knowledge, our meta-analysis is the first to demonstrate that the sepsis alert system was associated with a shorter time interval from the recognition of sepsis to the implementation of all sepsis bundle components.
Our analysis found that the sepsis alert system had more associations within the electronic alert systems than the nonelectronic systems.In our study, the electronic alert group had a lower mortality, shorter hospital LOS, and significantly better adherence to each bundle component.
However, the nonelectronic alert group showed no significant association with mortality or adherence to blood culture.The introduction of EHRs has enabled the application of electronic alerts as a sepsis alert system. 43,46Evidence has demonstrated the use of electronic alert systems across a spectrum of diseases. 47,48In high-volume, diverse patient scenarios, such as EDs, the need for distinct and efficient alert systems is crucial.The electronic alert system is integrated into the EHR and uses the information from the EHR to quickly alert clinicians to patients with sepsis, thereby improving their bundle adherence and reducing patient mortality rates.
However, careful consideration must be given to the potential for false-positive alarms, which vary significantly depending on the methods used.Our meta-analysis includes studies that reported a wide range of sensitivities for detecting sepsis. 27,35This variability underscores the persistent risk of false positives.Comprehensive research is essential to better understanding the impacts of sepsis alert systems, particularly focusing on the rate of false positives and their associated consequences, such as resource overutilization and the overprescription of antibiotics.

Limitations
This study had some limitations.First, the definition of sepsis was not uniform across the studies included in our systematic review and meta-analysis.This may be due to the retrospective observational design of most studies, which relied on criteria, such as systemic inflammatory response syndrome and quick sequential organ failure assessments, to define sepsis.Moreover, these variations may reflect the evolution of the definition of sepsis over time.However, we confirmed that the degree of heterogeneity was not a concern among studies regarding mortality as an outcome.

Conclusions
This systematic review and meta-analysis demonstrated the significant association of implementing sepsis alert systems in the ED with patient outcomes.These findings indicate that sepsis alert systems were not only associated with reduced mortality risk but also higher and quicker adherence to the sepsis bundle.These beneficial outcomes were more frequently observed in the electronic alert systems.The results of this study highlight the potential of sepsis alert systems as valuable tools for improving the outcomes of adult patients with sepsis in the ED, thus emphasizing the importance of their widespread implementation and integration into clinical practice.Given the significant heterogeneity of the studies, careful interpretation is required, and future research with more controlled environments is needed.

Figure 1. Flowchart of the Study Selection Process 3277 Records identified through database searching 4 Additional records identified through other sources 3024 Records
screened after duplicates removed 179 Full-text articles assessed for eligibility 22 Studies included in qualitative synthesis and quantitative synthesis (meta-analysis)

Table 1 .
Characteristics of Studies Included in the Meta-Analysis Abbreviations: ED, emergency department; EWS, early warning score; ICD-9, International Classification of Diseases, Ninth Revision; ICU, intensive care unit; qSOFA, quick sequential organ failure assessment; RETTS, rapid emergency triage and treatment system; SIRS, systemic inflammatory response syndrome.SI conversion factor: To convert lactate to millimoles per liter, multiply by 0.111.a SIRS criteria are body temperature greater than 38 °C or less than 36 °C; heart rate 2 less than 200 in the absence of pneumonia as infection source, creatinine greater than 2.0 mg/dL (to convert to micromoles per liter, multiply by 76.25), total bilirubin greater than 2 mg/dL (to convert to micromoles per liter, multiply by 17.104), platelet count less than 100 ×10 3 /μL (to convert to ×10 9 /L, multiply by 1), coagulopathy (international normalized ratio >1.5), evidence of hypotension or hypoperfusion (indicated as systolic blood pressure <90 mm Hg after 20 mL/kg crystalloid bolus or lactate Ն36.04 mg/dL).c Defined as systolic blood pressure 86 to 90 mm Hg with intravenous fluids or less than 86 mm Hg regardless of fluids; or blood oxygen saturation of 85% to 90% with supplemental oxygen or less than 85% without oxygen; or lactate greater than 18.02 mg/dL.d Severe sepsis and persistent hypotension or end organ dysfunction despite fluid resuscitation or vasopressors.e f Predeveloped logistic regression model composed of demographic data, vital signs, laboratory results, orders, and comorbidities.

Table 2 .
Association of Electronic Alert Systems With Adherence to Sepsis Bundle ProtocolsWe found that the implementation of the sepsis alert system was significantly associated with a lower mortality risk compared with the control group.A meta-analysis of 36 studies by Zhang et al 42 evaluated the effectiveness of the sepsis alert system in ED, general ward, and ICU settings.Zhang et al 42 reported a significant reduction in mortality (29%) with sepsis alert systems compared with Figure 3. Association of Sepsis Alerts With the Time to Each Sepsis Bundle Event in the Emergency Department a Statistically significant.bExpressedas risk ratio.c Expressed as standardized mean difference.JAMA Network Open | Critical Care Medicine Sepsis Alert Systems, Mortality, and Adherence in Emergency Departments JAMA Network Open.2024;7(7):e2422823.doi:10.1001/jamanetworkopen.2024.22823(Reprinted) July 22, 2024 7/13 Downloaded from jamanetwork.comby guest on 07/24/2024 Sepsis Alert Systems, Mortality, and Adherence in Emergency Departments not randomized and prone to confounding factors.Third, most management protocols included steps for sepsis management after sepsis alert system interventions.Consequently, clinical outcomes might be influenced by these interventions.To maximize the effectiveness of sepsis alert systems, it is crucial to consider the entire sepsis care process, from early recognition to timely treatment.Further research is needed to identify the specific interventions that should be implemented in conjunction with sepsis alert systems to optimize patient outcomes.Fourth, despite examining all bundle components, we could not demonstrate the results of vasopressor use.Only 2 studies assessed the use of vasopressors; however, they only reported whether vasopressors were used, without providing any information on their application in response to hypotension during or after fluid resuscitation.Fifth, while our study presents findings regarding the mean time to implementation of sepsis bundle components, it lacks comprehensive data on the proportion of patients whose care fully adhered to all aspects of the sepsis bundle within the critical first hour of recognition.Due to the diverse definitions used in the included studies, our analysis could not definitively determine complete adherence within the specified time frame.